Abstract

Phospholipase D2 (PLD2) has been found localized in low-density caveolin-rich membrane microdomains. Our previous study suggested that PLD2 and aquaporin 3 (AQP3) interact in these domains to inhibit keratinocyte proliferation and promote differentiation by cooperating to produce phosphatidylglycerol. To examine the effect of membrane microdomain localization on the PLD2/AQP3 signaling module and keratinocyte proliferation and differentiation, we treated mouse keratinocytes with 3 µM cell-permeable caveolin-1 scaffolding domain peptide or a negative control peptide and stimulated cell differentiation using a moderately elevated extracellular calcium concentration (125 uM) to maximally promote differentiation and phosphatidylglycerol production. Cell proliferation, differentiation, total PLD activity, phosphatidylglycerol levels, and AQP3 activity were monitored. The caveolin-1 scaffolding domain peptide itself had no effect on phosphatidylglycerol levels or keratinocyte proliferation or differentiation but prevented the changes induced by a moderately elevated calcium concentration, whereas a negative control did not. The caveolin-1 scaffolding domain peptide had little effect on total PLD activity or glycerol uptake (AQP3 activity). We conclude that the caveolin-1 scaffolding domain peptide disrupts the functional association between AQP3 and PLD2 and prevents both the inhibited proliferation and the stimulated differentiation in response to elevated extracellular calcium levels. The interaction of caveolin-1 and PLD2 is indirect (i.e., lipid mediated); together with the proliferation-promoting effects of caveolin-1 knockout on epidermal keratinocytes, we propose that the caveolin-1 scaffolding domain pepetide exerts a dominant-negative effect on caveolin-1 to alter lipid rafts in these cells.

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